Cellular processes such as cell adhesion, cytolinesis, cell motility, migration, and muscular contraction/relaxation require dynamic reorganization of the actin cytoskeleton. Activation of cyclic nucleotide signaling pathways in various cell types leads to profound alterations in the cytoskeleton, which include loss of central stress fibers and focal adhesion plaques; cytoplasmic retraction with the formation of thin processes; and rounding of the cell bodies (1). In aggregate, these changes lead to a star-shaped appearance that has been termed “stellation.”
The cyclic nucleotide signaling pathways include adenylate cyclase/cAMP/cAMP-dependent protein kinase (PKA) and guanylate cyclase/cGMP/cGMP-dependent protein kinase (PKG). These pathways converge at the phosphorylation of the small heat shock-related protein, HSP20 on serine 16 (2, 3).
We have previously demonstrated that HSP20 and certain peptides derived therefrom show promise as therapeutic agents for the following: (a) inhibiting smooth muscle cell proliferation and/or migration; (b) promoting smooth muscle relaxation; (c) increasing the contractile rate in heart muscle; (d) increasing the rate of heart muscle relaxation; (e) promoting wound healing; (f) reducing scar formation; (g) disrupting focal adhesions; (h) regulating actin polymerization; and (i) treating or inhibiting one or more of intimal hyperplasia, stenosis, restenosis, atherosclerosis, smooth muscle cell tumors, smooth muscle spasm, angina, Prinzmetal's angina (coronary vasospasm), ischemia, stroke, bradycardia, hypertension, pulmonary (lung) hypertension, asthma (bronchospasm), toxemia of pregnancy, pre-term labor and/or delivery, pre-eclampsia/eclampsia, intrauterine growth restriction, Raynaud's disease or phenomenon, hemolytic-uremia, non-occlusive mesenteric ischemia, anal fissure, achalasia, sexual dysfunction, migraine, ischemic muscle injury associated with smooth muscle spasm, vasculopathy, such as transplant vasculopathy, bradyarryhmia, bradycardia, congestive heart failure, stunned myocardium, pulmonary hypertension, and diastolic dysfunction. (See, for example, US 20030060399 filed Mar. 27, 2003; WO2004017912 published Mar. 4, 2004) However, these applications did not demonstrate that the activities of HSP20 result from specific protein-protein interactions with other molecules within the cell. The identification of specific proteins that HSP20 interacts with to carry out its cellular functions could lead to the design of improved HSP20-derived therapeutics.